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Dissertation
Hepatitis B virus X protein modulation of cell proliferation pathways is required for HBV replication in primary hepatocytes
Doctor of Philosophy (Ph.D.), Drexel University
21 Apr 2010
DOI:
https://doi.org/10.17918/00000769
Abstract
Worldwide there are over 350 million people who are chronically infected with the human Hepatitis B virus (HBV); chronic HBV infections are associated with the development of hepatocellular carcinoma (HCC). The results of various studies suggest that the HBV X protein (HBx) has a role in the development of HBV-associated HCC. HBx can regulate numerous cellular signal transduction pathways, including those that modulate cell proliferation. Many previous studies that analyzed the impact of HBx on cell proliferation pathways were conducted in established or immortalized cell lines and when HBx was expressed in the absence of HBV replication, and the precise effect of HBx on these pathways has often differed depending on experimental conditions. We have studied the effect of HBx on cell proliferation in cultured, primary rat hepatocytes, a biologically relevant system. We demonstrate that HBx, both alone and in the context of HBV replication, affected the levels and activities of various cell cycle regulatory proteins to induce normally quiescent hepatocytes to enter G1 phase of the cell cycle, but not proceed to S phase. We linked HBx regulation of cell proliferation pathways to cytosolic XIII calcium and activity of the mitochondria permeability transition pore (MPTP). Additionally, we have demonstrated that HBx stimulation of cell proliferation pathways, and HBx modulation of cytosolic calcium and the MPTP, are required for HBV replication. While it is unclear why HBx stimulates cell cycle entry, it may involve creating a more favorable environment for HBV replication. We observed that HBx increases the level of the catalytic subunit of ribonucleotide reductase, an enzyme that synthesizes dNTPs, and that modulation of this enzyme is required for HBV replication. Cumulatively, our studies suggest that HBx induces normally quiescent hepatocytes to enter, and stall in, G1 phase of the cell cycle, and that HBx regulates cell proliferation pathways by modulating cytosolic calcium and the MPTP. Moreover, induction of cell proliferation, cytosolic calcium, and MPTP activity are required for HBV replication in hepatocytes. These studies identify an essential function of HBx during HBV replication and a mechanism that may connect HBV infections to the development of HCC.
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Details
- Title
- Hepatitis B virus X protein modulation of cell proliferation pathways is required for HBV replication in primary hepatocytes
- Creators
- Tricia Leigh Gearhart
- Contributors
- Michael Bouchard (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 249 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014970185604721